Transcutaneous Electrical Nerve Stimulation (TENS) for Opioid-Induced Constipation in Palliative Care: A Systematic Review and Network Meta-Analysis

Background Opioid-induced constipation (OIC) has become increasingly prevalent with the rise of prescription opioid use, particularly in patients with advanced illnesses. Existing literature suggests that transcutaneous electrical nerve stimulation (TENS) could be applied to treat cancer pain and reduce OIC incidence. However, there need to be more systematic review studies on the effectiveness of TENS in treating OIC. Objective In order to fill the gap of TENS in treating OIC in current knowledge, we have conducted a systematic review and network meta-analysis. Methods The comprehensive computer retrieval PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM), and Wanfang Database were used to collect literature for relevant studies of TENS treatment of OIC, in accordance with the standard of literature filtering, data extraction, and quality evaluation. The data were meta-analysed using ReviewManager 5.3 software recommended by Cochrane. Results A total of 180 pieces of literature were yielded through original search. Based on the inclusion and exclusion criteria, a total of 9 articles were included in this study. Our analysis of seven studies has revealed that TENS (28.18%) significantly reduces the incidence rate of OIC compared to control (52.45%) (I2 = 57%, P=0.03; OR = 0.66 (95% CI, 0.53 to 0.82), Z = 3.70, P < 0.01). The results of two studies indicated that TENS significantly improved the quality of life compared to the control group (i.e., treatment-as-usual only) (I2 = 80%, P=0.03; OR = −1.91; 95% CI, −2.54 to −1.29, Z = 6.00, P < 0.01). Conclusion The administration of TENS therapy holds the potential to mitigate the occurrence of OIC and augment the quality of life for individuals suffering from cancer. Particularly, TENS therapy proves to be appropriate for propagation within community and domestic environments. Nevertheless, advanced clinical randomized controlled trials of superior quality are necessary to authenticate the comprehensive clinical efficiency and safety of this therapy. Further investigation is indispensable to comprehend its mechanism in greater detail and establish the optimum therapeutic strategy.


Introduction
Patients with advanced-stage cancer typically experience cancer-associated symptoms, which can considerably impair their quality of life [1]. Te prevalence of cancer pain has been estimated to range from 40 to 80%, with its incidence increasing as the disease progresses [2]. It may produce excruciating pain, seriously afecting their quality of life [3]. Te World Health Organization (WHO) recommended opioids as analgesics to treat cancer pain, and they are widely used clinically for managing chronic cancer pain [4]. However, previous studies have suggested that opioidinduced constipation (OIC) can occur in up to 90% of patients, which is often persistent [5,6]. Terefore, minimizing cancer pain and its side efects is essential to manage cancer pain. To treat OIC, pharmacological and nonpharmacological treatment approaches have been studied. Although the clinical use of oral laxatives or rectal administration can relieve constipation, their adverse reactions are noticeable, and their efectiveness is limited. Transcutaneous electrical nerve stimulation (TENS) is a safe, noninvasive, relatively inexpensive, and nonpharmacological approach as an adjunctive analgesic treatment for advanced cancer pain [7][8][9]. TENS involves a cutaneous electrode that is equivalent to needleless electroacupuncture. It can stimulate the release of endogenous neurotransmitters such as endorphin and dynorphin and enhance the maintenance of normal physiological movement of the gastrointestinal tract [10]. Several studies have suggested that TENS can signifcantly improve the clinical symptoms and quality of life in patients with OIC [11][12][13]. However, Nakano et al. [14] posit that while TENS can signifcantly reduce opioid side efects such as nausea, pain, and OIC, its efects on OIC treatment are not satisfactory.
Currently, a limited amount of literature is available on the use of TENS for treating OIC, and a systematic review of the research literature was not found. We conducted a systematic review and network meta-analysis to address this knowledge gap.

Search Strategy.
We systematically searched several databases, including PubMed, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), Chinese Biomedical (CBM), and Wanfang Database, from inception to July 1, 2022, without language restrictions. Te search terms included "cancer," "neoplasm," "tumor," "constipation," and "Transcutaneous Electric Nerve Stimulation." Te keywords were combined using Boolean searches and MeSH descriptors. Te detailed search strategy is shown in Table 1. Te search strategy was formulated by two independent researchers who conducted a pre-examination, checked, and fnalized the strategies before conducting a formal search. In the event of any disagreement, both researchers discussed and reached a consensus, and if necessary, a third party was consulted for a fnal decision.

Study Selection Criteria.
Te inclusion criteria for the study were as follows: (a) randomized controlled trials or other controlled studies; (b) cancer patients diagnosed with OIC, regardless of race, sex, age, disease course, and severity; (c) description of the opioid dosage; (d) the treatment group was treated with TENS, while patients in the control group received rehabilitation treatment but did not receive TENS therapy; (e) the results reported the incidence of constipation or constipation scores; (f ) double-blind and openlabel trial designs were eligible. Te exclusion criteria were: (a) non-English and non-Chinese language articles, abstracts from conferences, full texts without raw data for retrieval, duplicate publications, letters, and review articles; and (b) articles that did not meet the inclusion criteria.

Data Extraction and Quality Assessment.
Two reviewers independently extracted data from the studies and assessed their eligibility for inclusion based on the abovementioned criteria. Any discrepancies between the two reviewers were resolved through consensus or discussion with a third reviewer. Te extracted data included: (a) basic study information, such as frst author and publication year; (b) study characteristics, including sample size, patient age, analgesic measures, types of cancer, treatment time, TENSrelated information (electrical stimulation points, electrical nerve stimulator parameter setting, frequency); (c) primary outcome measures of interest, including the incidence of constipation or the efective rate of treating constipation, secondary outcome measures, such as quality of life scores, and the incidence of adverse reactions; and (d) relevant elements of the bias risk assessment.
Conducting randomized clinical trials of interventions such as TENS or acupuncture present challenges in achieving blinding, which refers to the extent to which participants and/or researchers must be made aware of which intervention is being administered. Blinding is crucial as it can minimize bias due to the expectations or preferences of participants and researchers. However, blinding may be difcult or impossible in some interventions, such as physical manipulation or sensory stimulation. Although such trials may not be blinded, they are still considered acceptable by researchers [15][16][17][18]. Te Cochrane collaboration tool is commonly used to assess selection bias in metaanalyses of randomized controlled clinical trials [19]. It evaluates whether data allocation was random and whether any baseline diferences between groups suggest issues with randomization [20]. Tis is precisely the objective of our study, and thus, we chose the Cochrane collaboration tool to evaluate the risk of bias. Two review authors evaluated the methodological quality of included trials and their risk of bias across seven domains, including allocation concealment, random sequence generation, incomplete outcome data, selective outcome reporting, blinding of participants and personnel, blinding of outcome assessment, and other biases, based on the Cochrane collaboration's tool [21].

Statistical Analysis.
We used RevMan 5.3 (Cochrane Collaboration) software to conduct the meta-analyses. For dichotomous variables, we used the odds ratio (OR) and 95% confdence interval (95% CI). Te choice between the fxed efect and random efect model in meta-analysis depended on the degree of heterogeneity among the studies, as determined by the previous literature [22,23]. Specifcally, we used the fxed efect model for meta-analysis if P > 0.10 and I 2 ≤ 50% and the random efect model if P ≤ 0.10 and I 2 > 50%. In cases where clinical heterogeneity was too signifcant or insufcient literature to perform a metaanalysis, we used descriptive analysis. We considered P < 0.05 to be a signifcant diference.

Results Included Studies.
In our initial search, we identifed 180 pieces of literature, out of which 31 were excluded due to duplication, resulting in a total of 149 studies for title and abstract screening. After this screening, 42 articles were selected for full-text reading, out of which 33 were excluded as they did not meet the eligibility criteria. Finally, a total of 9 studies that met the standards were included in the meta-analysis. A summary of the literature search process is presented in Figure 1. Te primary characteristics of the included articles are shown in Table 2, and the acupoints utilized in the included studies are shown in Figure 2.

Risk of Bias Assessment.
We assessed the risk of bias and concerns regarding the applicability of the included studies using the Cochrane collaboration tool (ROB 2 IRPG 2018 beta v6), and the results are reported in Figure 3. Overall, the included studies were of high quality, with only some concerns regarding allocation concealment, study subjects hiding, and researcher hiding being rated as a signifcant risk of bias. However, it is generally acceptable for these factors to be rated as high risk of bias because blinded studies involving TENS or acupuncture can be challenging to conduct [15][16][17][18].

Primary Outcomes: Incidence Rate of OIC or Efective Rate.
A total of seven studies (809 participants; TENS: 401, control: 408) that reported the incidence rate of OIC provided sufcient data for statistical pooling. Te test for the heterogeneity among the studies showed signifcant heterogeneity (P � 0.03; I 2 � 57%), and as such, the random-efects model was used. Te meta-analysis results are presented in Figure 4. Te sample size was 809, consisting of 401 cases (OIC occurred in 113 patients) and 408 controls (OIC occurred in 214 patients). Te heterogeneity, calculated using the I 2 statistic with a randomefect model, was I 2 � 57%, P � 0.03. Overall, TENS signifcantly reduced the incidence rate of OIC compared with the control (pooled OR � 0.66; 95% CI: 0.53-0.82, Z � 3.70, P < 0.01).
Two studies (449 participants; TENS: 222, control: 227) compared the efective rate of treating constipation between the TENS treatment group and the control group. Te test for the heterogeneity among the studies showed signifcant heterogeneity (P � 0.82; I 2 � 0%), and as such, the random-efects model was used. Te meta-analysis results showed in Figure 5. Te meta-analysis results showed no statistically signifcant efect of TENS in increasing the efective rate of treating OIC compared with control (lactulose oral solution) (I 2 � 0%; P � 0.82; OR � 1.08; 95% CI: 1.00-1.16, Z � 1.84, P � 0.07). (ii) Non-OIC (9 pieces); (iii) Animal Experiments (7 pieces); After screening titles and abstracts, 42 papers were selected and read in full text.

Discussion
TENS was employed to ameliorate the adverse efects of chemotherapy, such as nausea, insomnia, cachexia, and pain, in patients with advanced cancer. Although it cannot be considered a substitute for opioids and other pharmacological interventions, it can support palliative care [12]. Compared to the traditional acupuncture point treatment, TENS is uncomplicated, safe, reproducible, and more appropriate for long-term home patients who cannot take oral medications for self-management, deserving of clinical promotion. Te efcacy of TENS in cancer patients is not only limited to pain relief but also extends to mitigating other physical symptoms during palliative care, including constipation, fatigue, nausea, and vomiting, as reported in various studies [13,32,33]. Reportedly, 97% of patients with cancer and OIC experience moderate to severe constipation-related symptoms, despite the widespread application of laxatives [34]. However, the present meta-analysis fndings unveil that the incidence of OIC is 66%, and TENS markedly curtails the incidence rate of OIC compared to the control group. Te outcomes of this study should push for further research to compare the incidence rate of OIC and bowel function index across various types of cancer.
Te precise selection of points is paramount for the efcient employment of TENS in alleviating OIC or cancerrelated discomfort. According to the comprehensive review of nine OIC prevention studies, the Tianshu acupoint was identifed as the optimal point for selection, and a metaanalysis confrmed its efcacy in signifcantly reducing the incidence of OIC.
Point selection is essential for TENS to treat OIC or cancer pain. Te nine OIC prevention studies included in this review found that Tianshu acupoint was selected, and a meta-analysis showed that it could signifcantly reduce the incidence of OIC. Tere are few studies on TENS therapy or adjuvant therapy for OIC, and only 9 studies were searched in this study. Te dearth of knowledge on the specifc mechanisms of OIC, coupled with the numerous OIC cases, necessitates more in-depth and meticulous research in the future, such as stimulating diferent acupoints for the efect of comparative studies, diferent frequency stimulation effects of comparative studies, diferent types of cancer, and psychological interventions. Ideally, future studies should be randomized, double-blinded, and placebo-controlled to assess TENS' clinical efcacy and safety. However, this is an     Evidence-Based Complementary and Alternative Medicine enormous challenge, as the blindness of TEAS treatment seems impossible, given that patients will eventually know whether they receive treatment. Nakano et al. [12] studied the constipation of patients in TENS and non-TENS phases, but whether there is a diference in the extent of the constipation of cancer is controversial. We recommend random TENS treatment, that is, a random selection of patients after admission for fve days of TENS or fve days of lactulose oral liquid treatment, which may be more adept at reducing the error. TENS may possess a mechanism of action akin to that of acupuncture. Te mechanism of pain treatment via acupuncture centers around the activation of opioid receptors and neuropeptide genes [35]. Acupuncture regulates braingut peptide metabolism by controlling the functional activity of the central nervous system, which in turn regulates the brain-gut axis, possibly being the mechanism of acupuncture. Furthermore, a crucial element of the acupuncture efect is regulating and repairing the nervous system, regulating emotions, and mitigating patients' emotions [36][37][38][39]. Research needs to be done more regarding the mechanism of TENS or acupuncture for treating OIC.
Chemotherapy patients often endure the pain caused by chemotherapy-induced adverse reactions, and due to the nature of their treatment, they commonly reside in their homes during the chemotherapy interval. Consequently, nurses are faced with the challenge of monitoring their condition and providing adequate care. Te evolution of family rehabilitation and community health care as a means of continuing care has been slow, and nursing personnel generally lack a comprehension of the concept of continuing care. Given the remedial efects of acupuncture on analgesia, there has been a growing acceptance of acupuncture treatment. TENS, a new type of acupuncture, has a similar analgesic efect to acupuncture [40] but with the advantage of being noninvasive, thus making it more readily accepted [41,42]. Providing appropriate physical treatment services, including early intervention and community follow-up, can signifcantly aid in maintaining the functional independence and quality of life of patients receiving palliative treatment [43].
Several limitations were present in this meta-analysis. Firstly, it is noteworthy that meta-analysis represents secondary research, and the outcome signifcantly relies on primary studies [21], inevitably leading to certain limitations. Secondly, sample sizes in some of the included studies and subgroup analyses were comparatively small. Consequently, the limited sample sizes might bias the outcome. Tirdly, researchers fnd it challenging to guarantee strict consistency when they conduct research under the control of related factors criteria, such as age range, physical condition, types of cancer, and cancer stages of the included populations, which will afect the research outcome some degree. Fourthly, the publication bias test displayed no evidence of publication bias.
Nevertheless, this research conducted a comprehensive retrieval with a language limited to Chinese and English. Hence, it may lead to corresponding language bias, even though it is understood that accessibility is limited to databases and language ability. Fifthly, the lack of standardization is an issue. Currently, there is no standardized protocol for TENS treatment for OIC. Te optimal frequency, intensity, and duration of treatment vary depending on the individual's response. Most studies on TENS have focused on treating pain rather than constipation. In conclusion, we must take the fndings of this study into account.

. Conclusion
With the progress of technology, it is possible to individualize TENS therapy based on an individual's response. Especially, TENS is suitable for promotion in the community and home settings. In conclusion, TENS can potentially treat OIC, but the evidence of its efcacy is limited. Further research is essential to comprehend its mechanism better and establish the optimal therapeutic approach. TENS can be combined with other therapies to provide complete relief for OIC.

Conflicts of Interest
Te authors declare that there are no conficts of interest.